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Abstract

Background

In recent years, neuroimaging techniques such as functional magnetic resonance imaging
(fMRI) and positron emission tomography (PET) have played a significant role in elucidating
the neural underpinnings of posttraumatic stress disorder (PTSD). However, a detailed
understanding of the neural regions implicated in the disorder remains incomplete
because of considerable variability in findings across studies. The aim of this meta-analysis
was to identify consistent patterns of neural activity across neuroimaging study designs
in PTSD to improve understanding of the neurocircuitry of PTSD.

Methods

We conducted a literature search for PET and fMRI studies of PTSD that were published
before February 2011. The article search resulted in 79 functional neuroimaging PTSD
studies. Data from 26 PTSD peer-reviewed neuroimaging articles reporting results from
342 adult patients and 342 adult controls were included. Peak activation coordinates
from selected articles were used to generate activation likelihood estimate maps separately
for symptom provocation and cognitive-emotional studies of PTSD. A separate meta-analysis
examined the coupling between ventromedial prefrontal cortex and amygdala activity
in patients.

Results

Results demonstrated that the regions most consistently hyperactivated in PTSD patients
included mid- and dorsal anterior cingulate cortex, and when ROI studies were included,
bilateral amygdala. By contrast, widespread hypoactivity was observed in PTSD including
the ventromedial prefrontal cortex and the inferior frontal gyrus. Furthermore, decreased
ventromedial prefrontal cortex activity was associated with increased amygdala activity.

Conclusions

These results provide evidence for a neurocircuitry model of PTSD that emphasizes
alteration in neural networks important for salience detection and emotion regulation.

Keywords:

Background

In the aftermath of highly distressing and shocking events such as combat, genocide,
and rape, a subset of individuals develop posttraumatic stress disorder (PTSD), which
is characterized by distressing memories of the event, physiological hyperarousal,
and impairment in daily functioning. With the growing interest in PTSD due in part
to its high prevalence among veterans of the Iraq and Afghanistan wars, there is an
urgency to understand the neural pathogenesis of the disorder. Neuroimaging studies
have been conducted to examine brain regions involved in PTSD [1-26]. Based on these findings and the non-human animal literature, the prevailing neurocircuitry
model of PTSD suggests that PTSD can be understood in terms of circuits involved in
fear conditioning in the brain. Specifically, this model suggests that heightened
amygdala activity gives privileged status to feared and threatening stimuli. Whereas
the ventromedial prefrontal cortex would normally temper amygdala activity, abnormal
function of this region reduces regulation of amygdala output [27]. Furthermore, altered hippocampal function may result in impaired ability to discern
safe from dangerous contexts.

The aforementioned brain regions, which play a key role in nonhuman animal fear conditioning
[28], likely play an important role in PTSD. PTSD is more likely to develop following
highly fear-provoking and life-threatening events than less intense events [29]. Influential psychological theories of PTSD have emphasized the role of fear structures
and fear conditioning in the development and maintenance of the disorder [30,31]. Furthermore, exposure therapy, which involves the principles of extinction learning
[30], is one of the most effective therapeutic interventions for PTSD.

However, fear conditioning models are limited in their ability to explain the full
range of human experience and emotion. Fear conditioning can occur outside of conscious
awareness, yet conscious processes such as voluntary and effortful avoidance of thoughts
and memories of the trauma play a vital role in the development and maintenance of
the disorder [32]. This has led to growing supposition that fear-circuitry models are unable to fully
account for the heterogeneity of symptoms following a traumatic event [33] and that anxiety and fear may not be the central components in explaining PTSD symptomatology
as previously believed [34]. Accordingly, the proposed revision of the Diagnostic and Statistical Manual (DSM-V)
may now recognize negative cognitions and persistent negative mood states as key symptoms
of the diagnosis [35], suggesting that other emotions such as dysphoria are important in the development
and maintenance of the disorder in addition to fear. Therefore, a primary goal of
the present study was to examine patterns of brain activation in neuroimaging studies
of PTSD that may provide a more complete understanding of the neural circuitry of
PTSD.

In the present study, we performed a quantitative meta-analysis of neuroimaging studies
in PTSD using activation likelihood estimation (ALE). This method calculates the probability
that a given voxel is activated consistently across studies rather than a single study
[36] and therefore provides a more objective measure of brain activity in PTSD than qualitative
reviews. Although there have been two prior functional neuroimaging meta-analyses
in PTSD [37,38], the present study includes more recent studies, focuses solely on adult PTSD, and
considers separately the effects of study type (symptom provocation versus cognitive-emotional)
and neuroimaging analysis type (whole-brain voxel-wise analysis versus region-of-interest
[ROI] analysis). Symptom provocation studies are designed to elicit trauma-related
symptoms whereas cognitive-emotional studies include emotional stimuli (e.g., fearful
face) but do not explicitly cue the patient to their traumatic event. In contrast
to previous meta-analyses in PTSD, the current study separates symptom provocation
and cognitive-emotional studies to examine the neural correlates of two primary characteristics
of PTSD: specific recall of a traumatic event (symptom provocation) and emotional
response generalization (cognitive-emotional studies). Furthermore, examining results
from whole-brain voxel-wise analyses separately from ROI analyses may provide greater
insight whether the regions typically targeted in ROI studies (e.g., the amygdala)
are also robustly active when taking into account all voxels in the brain. ROI analyses
restrict statistical analysis to the small number of a priori defined voxels, reducing
the need for more stringent correction for multiple comparisons; thus, ROI studies
are not entirely comparable to studies employing whole-brain voxel-wise statistics.
In the present study, we examined the results from ROI studies as they comprise a
significant proportion of imaging studies in PTSD, with the recognition that whole
brain voxel-wise analyses represent a less biased statistical approach. Finally, we
performed a separate meta-analysis to test the fear-model hypothesis that hypoactivity
in the ventromedial prefrontal cortex is associated with hyperactivity in the amygdala,
reflecting insufficient inhibition of prefrontal cortex over the amygdala.

Methods

Article selection

Using keywords “PTSD,” “neuroimaging,” “fMRI,” and “PET,” a literature search in PubMed
and Published International Literature on Traumatic Stress (PILOTS) was conducted
for PET and fMRI studies of adult PTSD that were published before February 2011. The
article search resulted in 79 functional neuroimaging studies. Included studies contrasted
a traumatic or negative emotional condition with a resting baseline, positive condition,
or neutral condition, conducted between-group analyses using subtraction methodology,
and reported between-group peak activation coordinates in standard space. For relevant
articles that did not report whole-brain results, the authors were contacted to request
activation coordinates [6,10]. Case studies were excluded [39,40] as well as studies examining PTSD and co-morbidity with other disorders, although
an exception was made for major depressive disorder (MDD) because of its high co-morbidity
with PTSD [13]. Based on these inclusion and exclusion criteria, 26 adult PTSD neuroimaging studies
reporting results from 342 patients and 342 controls remained in the analyses (see
Table 1).

Inclusion/exclusion criteria for activation foci

For each of the articles listed in Table 1, significant peak activation coordinates were extracted for negative > other (baseline,
positive, or neutral) between-group contrasts (PTSD > Controls; Controls > PTSD).
When coordinates for more than one type of negative > other contrast were reported
in the same study, only one contrast was included to avoid using foci from the same
participants twice [4,9,16,25]. In these cases, the selected contrast compared a trauma-specific or fear-inducing
condition with a neutral condition. If a study conducted a whole-brain and a ROI analysis
[8,9,12,26], coordinates from both analyses were included provided that the ROIs were not reported
in the whole-brain results [8,9,26].

In studies that included two levels of control groups (e.g., healthy controls and
trauma-exposed controls) or PTSD patients (e.g., PTSD with MDD versus PTSD without
MDD), only foci from one of the between-group comparisons were used (i.e., between-group
foci for PTSD vs. traumatized controls [5,8] and PTSD without co-morbidity vs. controls [13]). Following inclusion and exclusion of coordinates, 218 between-group activation
foci remained (Table 2).

Meta-analyses

Coordinate-based random-effects meta-analyses were conducted using GingerALE software
version 2.1 (http://brainmap.org/ale/webcite). Coordinates reported in MNI space were converted to Talairach space using the Lancaster
transform [41] as implemented in GingerALE. Coordinates from symptom provocation and cognitive-emotional
tasks were first combined to examine the neural regions involved across tasks and
then were analyzed separately to examine differences between the two design types.
A replicate set of analyses was performed that included ROI-based studies. Differences
in the whole-brain voxel-wise results with the inclusion of ROIs, when present, are
noted in the tables and results.

For each analysis reported, peak activation coordinates were smoothed using a three-dimensional
Gaussian filter and transformed into Gaussian probability distributions. These probability
distributions were combined to generate whole-brain statistical maps of the ALE values
on a voxel-wise basis. ALE statistics calculated the probability that at least one
of the foci lay within each voxel and, therefore, the likelihood that each voxel was
activated across all studies included in the analysis. The ALE statistic maps were
compared with a null-distribution of random spatial associations between experiments
(random-effects model) to assess for above chance clustering between experiments using
a threshold at false discovery rate (FDR) corrected P < 0.05 and a cluster-extent of 100 mm3.

To explore the hypothesis that activity in the ventromedial prefrontal cortex and
the amygdala was inversely related, we first identified whole-brain studies that reported
increased ventromedial prefrontal cortex activity in controls relative to PTSD patients
(which would suggest that this region was hypoactive in PTSD) and also reported regions
of increased activity in PTSD relative to controls. Six studies were identified that
met these criteria [1,11,12,21-23]. A meta-analysis was performed on the coordinates from these studies for the PTSD > Control
contrast. Thus, we examined the regions that were hyperactive in PTSD when the ventromedial
prefrontal cortex was hypoactive. Due to the small number of studies included, the
analysis was thresholded at FDR corrected P < 0.05 and a less conservative cluster-extent of 40 mm3 (i.e., 5 contiguous voxels) was used.

Results

Separate meta-analyses were run to examine the neural activity across and within symptom
provocation and cognitive-emotional tasks in PTSD. Because of the variability in naming
conventions of medial prefrontal cortex regions across different studies, activated
regions are listed in the text and tables both by their structure specific name (e.g.,
medial frontal gyrus) and a general name signifying their contribution to a broader,
less defined area (e.g., ventromedial prefrontal cortex which broadly includes the
pregenual and subgenual anterior cingulate cortex, medial orbitofrontal cortex, and
the ventral part of the medial prefrontal cortex).

Common activations for PTSD across tasks

The regions that were hyper- and hypoactive when studies were collapsed across task
type (i.e., symptom provocation and cognitive-emotional) in PTSD relative to control
subjects are reported in Table 3. We defined hyperactivity in PTSD as the results stemming from the PTSD > Control
contrast and hypoactivity in PTSD as brain regions active from the Control > PTSD
contrast. Patients with PTSD showed hyperactivation in the mid- and dorsal anterior
cingulate (Figure 1A), left superior temporal gyrus, and left supplementary motor area. Robust bilateral
amygdala and left dorsomedial prefrontal cortex activity was observed when ROI studies
were included (Figure 1)B.

Notably, there were several regions of hypoactivation in PTSD relative to controls
including the medial frontal gyrus (ventromedial prefrontal cortex; Figure 1B), thalamus, right inferior frontal gyrus (Figure 1B), and right middle temporal gyrus. When ROI studies were included, the results remained
consistent with additional activity observed in the pregenual anterior cingulate cortex
(Table 3).

Symptom provocation studies

A meta-analysis of symptom provocation designs was conducted to reveal the regions
that were involved in reliving one’s traumatic event (Table 4). The regions consistently hyperactivated in PTSD were the mid- and dorsal anterior
cingulate cortex. By contrast, widespread hypoactivity was observed, including the
medial frontal gyrus (ventromedial prefrontal cortex), right inferior frontal gyrus,
and right precuneus. These results were unchanged with the inclusion of ROI studies.
Figure 2 displays brain activation separately for symptom provocation and cognitive-emotional
studies.

Ventromedial prefrontal cortex meta-analysis

We next performed a meta-analysis on regions that were hyperactive in PTSD within
studies that reported decreased ventromedial prefrontal cortex activity (see Methods).
The analysis showed that when the ventromedial prefrontal cortex was hypoactivated,
greater amygdala activation was observed in PTSD, supporting the hypothesis that activity
in the ventromedial prefrontal cortex and amygdala are inversely related. Other regions
that showed increased activity included the right middle and inferior temporal gyrus,
left superior temporal gyrus, bilateral precuneus, and right putamen (Table 5).

Discussion

The present study used quantitative meta-analysis to examine the pathophysiology of
PTSD. The results confirmed involvement of a subset of regions implicated in fear-circuitry
models of PTSD, including robust hyperactivity in the dorsal anterior cingulate cortex,
hypoactivity in the ventromedial prefrontal cortex in PTSD, and an inverse relationship
between activity in the ventromedial prefrontal cortex and amygdala. However, additional
regions were found to be hyper- and hypoactive in PTSD, suggesting that a broader
view of the neural circuitry of PTSD should be considered. Collapsing across symptom
provocation and cognitive-emotional studies, the whole-brain voxel-wise analysis revealed
hyperactivation of the mid/dorsal anterior cingulate cortex, supplementary motor area,
and superior temporal gyrus in PTSD. These regions have been previously shown to be
part of a putative ‘salience network’ that processes autonomic, interoceptive, homeostatic,
and cognitive information of personal relevance [42,43]. Ultimately, the salience network helps an organism evaluate whether stimuli in the
environment should be approached or avoided. Importantly, activity in this salience
network is positively correlated with anxiety [43]. We propose that in PTSD, the behavioral manifestation of increased output of the
salience network may provide privileged cognitive resources to a broad range of salient
stimuli leading to hypervigilance and disruption of goal-directed activity. This notion
is consistent with observations in PTSD patients of deficits in working memory for
not only trauma-related negative distractors, but also neutral distractors [44], suggesting that a variety of stimuli become potentially salient for patients with
PTSD. From this viewpoint, negative emotions other than fear can be associated with
the disorder, as long as they are salient and associated with a stress response.

The dorsal anterior cingulate cortex is a key node in the salience network. Earlier
conceptualizations of the region suggested that its role was primarily in “cold” cognitive
processes, in contrast to the ventral aspects of the anterior cingulate cortex that
were thought to be involved in affective processing [45]. However, more recent data have not corroborated a cognitive versus affective dissociation.
Recent reviews have called attention to the involvement of the dorsal anterior cingulate
cortex in PTSD [46,47], which may subserve learned fear, fear appraisal and expression, and sympathetic
activity [48]. More broadly, dorsomedial prefrontal regions (including the dorsal anterior cingulate
cortex) have been associated with appraisal and evaluation whereas ventromedial prefrontal
regions are associated with regulatory functions. This dissociation is consistent
with the findings reported here, where more dorsal prefrontal regions, including the
dorsomedial prefrontal cortex and mid/dorsal anterior cingulate cortex were active
in patients with PTSD and may suggest heightened appraisals of potential threats in
the environment, whereas hypoactivity in ventromedial prefrontal regions may reflect
dysfunction in emotion regulation.

Interestingly, the present results highlight the contribution of the mid-cingulate
in PTSD, adding to the growing evidence that this region plays an important role in
this disorder [49-51] and may be important for fear conditioning [52]. The dorsal anterior cingulate spans a large area, encompassing BAs 24, 32, and 33.
Whereas a more anterior portion of the dorsal anterior cingulate was activated in
both PTSD patients and control subjects in the present meta-analysis, a more posterior
region was hyperactivated only in PTSD. A previous study demonstrated that individuals
with severe PTSD symptomatology activated the mid/dorsal anterior cingulate to a greater
extent than controls during an emotional oddball task, suggesting that distracting
stimuli are given attentional preference at the expense of a goal-relevant task in
PTSD [49]. These findings provide converging evidence for the role of the mid/dorsal anterior
cingulate cortex in salience processing. Another region in the salience network, the
amygdala, was observed only when using a less stringent spatial extent in the whole-brain
analysis or when considering ROI analyses. The amygdala is notoriously difficult to
image due to vulnerability to susceptibility artifact and its relatively small volume,
which could account for lack of robust findings in the whole-brain analysis. Alternatively,
it is possible that the amygdala is not as central of a region in PTSD as current
neurocircuitry models suggest, consistent with previous meta-analysis data showing
that the amygdala is more frequently active in patients with social anxiety disorder
and specific phobia than PTSD [37].

With the addition of ROI analyses, amygdala activity was observed for cognitive-emotional
tasks but not symptom provocation tasks, suggesting that the type of task employed
within a study influences amygdala activity in PTSD. There is emerging recognition
that the amygdala may play a more general role in processing ambiguous and salient
stimuli in the environment [53-55], of which fear may be one particularly potent instance. The amygdala, which is composed
of several distinct but highly interconnected nuclei, is not specific to fear states
but is also activated for unusual and novel stimuli [56] and unpredictability [57]. Therefore, the stimuli and study designs employed during cognitive-emotional studies
of PTSD, which often present novel and ambiguous stimuli intermittently, may evoke
more central involvement of the amygdala than autobiographical trauma scripts, which
were often familiar and unambiguous from the start. Other explanations for the lack
of amygdala activity in symptom provocation designs are less likely. Both the symptom
provocation designs and the cognitive-emotional ROI studies (in which amygdala activity
was observed most robustly) were block designs; therefore, the results are unlikely
to be attributable to differences in neuroimaging experimental design (i.e., event-related
vs. block designs). Furthermore, the majority of both symptom provocation and cognitive-emotional
studies were fMRI rather than PET, suggesting that the difference is not due to imaging
modality. The discrepancy in amygdala activity for cognitive-emotional and symptom
provocation studies underscores the importance of considering the cognitive task when
interpreting activation differences (or lack thereof) in the amygdala in PTSD and
control participants.

In the present study, widespread hypoactivity in prefrontal cortex in PTSD was observed,
including both medial and lateral regions. Notably, hypoactivity in the ventromedial
prefrontal cortex was present in both symptom provocation and cognitive-emotional
study designs. To examine the relationship between the ventromedial prefrontal cortex
and amygdala, we performed a meta-analysis that identified regions of hyperactivity
within a subset of studies that showed a decrease in ventromedial prefrontal cortex
activity in PTSD patients. We reasoned that under conditions of diminished ventromedial
prefrontal cortex activity, which may signify reduced top-down governance of interconnected
regions, we would observe greater amygdala activity. The results showed that when
the ventromedial prefrontal cortex was hypoactive, the amygdala, putamen, and temporal
cortex were hyperactivated. These results support the notion that a consequence of
hypoactivity of the ventromedial prefrontal cortex may be greater responsivity of
the amygdala in the face of negative information. Although the direction of this effect
cannot be determined conclusively because the neural connections between the amygdala
and ventromedial prefrontal cortex are bidirectional, there is a well-established
literature showing the involvement of ventromedial prefrontal cortex in regulatory
control across species [58]. It is important to note that the ventromedial prefrontal cortex is not a single
entity, but rather is composed of multiple distinct regions (i.e., subgenual and pregenual
anterior cingulate cortex, medial portions of orbitofrontal gyrus, and medial frontal
gyrus) that subserve a variety of functions. For instance, the non-human animal literature
suggests that bordering divisions within ventromedial prefrontal cortex may be responsible
for both inhibition and facilitation of autonomic arousal [58]. This may help to explain why some studies of PTSD show increased activation in this
region [59] and suggests that a more fine-grained analysis is required to better elucidate the
various functions of the ventromedial prefrontal cortex. Nevertheless, the results
of the current meta-analysis show robust hypoactivation in the ventromedial prefrontal
cortex consistent across task type, underscoring its hypothesized role in regulatory
control.

Importantly, additional prefrontal cortex regions such as the inferior frontal gyrus
were hypoactivated in PTSD. This finding is notable as previous work has implicated
the role of inferior frontal gyrus in emotion regulation, including inhibition from
emotional distraction [60] and emotional thought suppression [61]. Moreover, the inferior frontal gyrus is purported to be involved in a network of
lateral prefrontal cortex regions involved in changing one’s negative thoughts to
reduce the impact of negative feelings (i.e., cognitive reappraisal) [62]. Although speculative, it is possible that decreased activity in lateral prefrontal
cortex may reflect PTSD patients’ difficulty challenging negative thoughts to cope
with emotional stimuli. Contemporary psychological models of PTSD highlight the role
of negative appraisals and emotion regulation in the etiology and maintenance of PTSD.
One of the most successful psychosocial interventions for PTSD, cognitive processing
therapy, is based upon the notion that faulty cognitions and interpretation surrounding
the traumatic event interferes with the natural recovery process after a trauma [63]. For example, a female rape victim who misattributes blame to herself for attending
a party where the rape occurred may then mistrust her decisions in every aspect of
her life, leading to experiential avoidance and withdrawal from social relationships.
Research has supported the notion that negative self-appraisals are associated with
PTSD symptom maintenance [64] and therefore the DSM-V may now include the presence of negative cognitions as a
core feature of the disorder [35]. Cognitive processing therapy encourages the patient to adopt a more balanced view
of the circumstances surrounding the traumatic event, as well as current personal
events by challenging negative thoughts. Given the present results, future studies
should examine whether individuals who benefitted from cognitive processing therapy
recruit the inferior frontal gyrus to a greater extent compared to pre-therapy, as
well as compared to individuals who did not benefit from therapy.

Limitations

A constraint of the current study is the availability of studies that met our criteria
for inclusion into the analyses. Although the literature search started with 79 studies,
the exclusion of studies that did not include stereotaxic coordinates likely reduced
our power to detect less robust activations. Although the number of foci included
in this study is more than the minimum recommended for a meta-analysis, it remains
an open question whether a larger sample will reveal additional networks central to
the PTSD diagnosis. For example, amygdala activity was observed in the PTSD group
only when considering ROI analyses or using a less stringent spatial extent. Therefore,
the limited number of studies available for the meta-analysis may have had an impact
on the ability to detect amygdala activity within the whole-brain analysis. Activity
in another key node within the salience network, the anterior insula, was observed
in the PTSD group using a less stringent cluster threshold (FDR corrected, P < 0.05, cluster-extent = 24 mm3). Future studies could isolate resting-state networks as a more powerful and robust
method towards understanding the functional connections between nodes of the salience
network in PTSD. Interestingly, a recent resting-state study in PTSD revealed greater
connectivity between the amygdala and insula in patients with PTSD than trauma-exposed
controls [65]. The results are consistent with the notion that key nodes within the salience network
are highly coactive in PTSD and may underlie the hallmark symptoms of the disorder.

Although there is convincing evidence that the hippocampus becomes dysfunctional as
a result of chronic stress [66] and activity in this region has shown to be negatively correlated with arousal symptoms
in PTSD [67], hippocampal activity was not observed in the present meta-analysis making it unclear
how this region contributes to neurocircuitry models of PTSD. Many of the tasks included
in this meta-analysis were not optimal for eliciting hippocampal activity and those
that do examine hippocampal function in PTSD show mixed results. There is a growing
functional neuroimaging literature examining learning and memory in PTSD, which may
clarify the role of hippocampus given that these types of paradigms traditionally
activate the hippocampus in healthy individuals.

Finally, working with a limited sample required inclusion of studies with patients
on medication and/or co-morbid depression. As additional studies are published and
software development continues, future meta-analyses may be able to focus exclusively
on PTSD or include depression and medication status as covariates in the analyses.

Conclusions

The goal of the present meta-analysis was to examine the neurocircuitry of PTSD by
considering a set of studies that were diverse in terms of functional imaging modality,
study design, and PTSD trauma type. The results provide evidence for hyperactivation
of regions important for vigilance and salience detection, and hypoactivation of regulatory
networks engaged in regulation of autonomic arousal and cognition. The key salience
network regions that appear to be important in PTSD include the dorsomedial prefrontal
cortex (including mid/dorsal anterior cingulate cortex), supplementary motor area,
and superior temporal gyrus.

Furthermore, regulatory control regions include two primary networks that appear to
be dysfunctional in PTSD, including ventromedial prefrontal cortex control over the
amygdala and lateral prefrontal regions putatively involved in modification of thought
and inhibition of distracting emotions. This model is consistent with the findings
that therapies designed to both extinguish fear responses and promote emotion regulation
through challenging negative cognitions are helpful for the treatment of PTSD.

Competing interests

The author(s) declare that they have no competing interests.

Authors’ contributions

Ms. Amanda Mikedis conducted a literature review, performed data analysis, and assisted
in writing the Methods section. Dr. Jasmeet Hayes and Dr. Scott Hayes helped with
the literature review and data analysis, and wrote the paper. All authors read and
approved the final manuscript.

Acknowledgements

We would like to thank Drs. Marcella Brunetti and Ruth Lanius for providing unpublished
activation coordinates for inclusion in the current meta-analysis, and Dr. Lisa Shin
for providing insightful comments on the manuscript. This work was supported by the
National Institutes of Health, National Institutes of Mental Health [grant number
K23 MH084013 awarded to JPH] and the Department of Veterans Affairs, Veterans Health
Administration, Rehabilitation Research & Development Service [grant number CDA E7822W
awarded to SMH]. These funding sources had no further role in the study analysis,
interpretation of the data, writing of the report, or approval of the paper.